The present invention relates to new anticholinergics of general formula 1: 
wherein A, Xxe2x88x92 and the groups R1, R2, R3, R4, R5, R6 and R7 may have the meanings given in the claims and specification, processes for preparing them as well as their use as medicaments.
Anticholinergics may be used to therapeutic effect in a wide range of illnesses. Special mention should be made, for example, of the treatment of asthma or COPD (chronic obstructive pulmonary disease). For treating these complaints, WO 92/16528 proposes anticholinergics which have a scopine, tropenol or tropine basic structure.
The underlying objective of WO 92/16528 is the preparation of anticholinergically effective compounds which are characterised by their long-lasting activity. To achieve this aim WO 92/16528 discloses, inter alia, benzilic acid esters of scopine, tropenol or tropine.
For treating chronic diseases it is often desirable to prepare medicaments with a longer duration of activity. As a rule, this ensures that the concentration of the active substance in the body needed to achieve the therapeutic effect is guaranteed for a longer period without the need to re-administer the drug at frequent intervals. Moreover, giving an active substance at longer time intervals contributes to the wellbeing of the patient to a high degree. It is particularly desirable to prepare a pharmaceutical composition which can be used therapeutically by administration once a day (single dose). The use of a drug once a day has the advantage that the patient can become accustomed relatively quickly to regularly taking the drug at certain times of the day.
In order to be used as a medicament taken once a day, the active substance to be given must meet particular requirements. First of all, the onset of the desired activity should take place relatively quickly after administration of the drug and ideally should have as constant an effect as possible over a subsequent fairly long period of time. On the other hand, the duration of activity of the drug should not substantially exceed a period of about one day. Ideally, an active substance has an activity profile such that the preparation of a drug for administration once a day, which contains the active substance in therapeutically beneficial doses, can be deliberately controlled.
It has been found that the benzilic acid esters of scopine, tropenol and tropine disclosed in WO 92/16528 do not meet these stringent requirements. Because of their extremely long period of activity, which significantly exceeds the above-mentioned period of about one day, they cannot be used therapeutically for administration in a single dose per day.
The aim of the present invention is therefore to provide new anticholinergics which, by virtue of their activity profile, make it possible to prepare a drug for administration once a day. A further objective of the invention is to prepare compounds characterised by a relative rapid onset of activity. The invention further sets out to provide compounds which, after a rapid onset of activity, have as constant an activity as possible over a subsequent lengthy period of time. A further aim of the invention is to provide compounds whose duration of activity does not substantially exceed a period of about one day in therapeutically beneficial doses. Finally, the invention sets out to provide compounds which have an activity profile which ensures good control of the therapeutic effect (i.e. total therapeutic effect without side effects caused by a build-up of the substance in the body).
Surprisingly, it has been found that the above objectives are achieved by means of compounds of general formula 1 wherein the group R7 does not denote hydroxy.
Accordingly the present invention relates to compounds of general formula 1: 
wherein
A denotes a double-bonded group selected from among: 
Xxe2x88x92 denotes anion with a single negative charge,
R1 and R2 denote C1-C4-alkyl, which may optionally be substituted by hydroxy or halogen;
R3, R4, R5 and R6, which may be identical or different, denote hydrogen, C1-C4-alkyl, C1-C4-alkyloxy, hydroxy, CF3, CN, NO2 or halogen;
R7 denotes hydrogen, C1-C4-alkyl, C1-C4-alkyloxy, C1-C4-alkylene-halogen, halogen-C1-C4-alkyloxy, C1-C4-alkylene-OH, CF3, xe2x80x94C1-C4-alkylene-C1-C4-alkyloxy, xe2x80x94Oxe2x80x94COC1-C4-alkyl, xe2x80x94Oxe2x80x94COC1-C4-alkyl-halogen, xe2x80x94Oxe2x80x94COCF3 or halogen, while 
if A denotes
R1 and R2 denote methyl and
R3, R4, R5 and R6 denote hydrogen,
R7 cannot also be hydrogen.
Preferred compounds of general formula 1 are those wherein
A denotes a double-bonded group selected from among: 
Xxe2x88x92 denotes an anion with a single negative charge selected from among chloride, bromide, methylsulphate, 4-toluenesulphonate and methanesulphonate, preferably bromide,
R1 and R2 which may be identical or different denote a group selected from among methyl, ethyl, n-propyl and iso-propyl, which may optionally be substituted by hydroxy or fluorine, preferably unsubstituted methyl;
R3, R4, R5 and R6, which may be identical or different, denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CN, CF3 or NO2;
R7 denotes hydrogen, methyl, ethyl, methyloxy, ethyloxy, xe2x80x94CH2xe2x80x94F, xe2x80x94CH2xe2x80x94CH2xe2x80x94F, xe2x80x94Oxe2x80x94CH2xe2x80x94F, xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94F, xe2x80x94CH2xe2x80x94OH, xe2x80x94CH2xe2x80x94CH2xe2x80x94OH, CF3, xe2x80x94CH2xe2x80x94OMe, xe2x80x94CH2xe2x80x94CH2xe2x80x94OMe, xe2x80x94CH2xe2x80x94OEt, xe2x80x94CH2xe2x80x94CH2xe2x80x94OEt, xe2x80x94Oxe2x80x94COMe, xe2x80x94Oxe2x80x94COEt, xe2x80x94Oxe2x80x94COCF3, xe2x80x94Oxe2x80x94COCF3, fluorine, chlorine or bromine.
Particularly preferred are compounds of general formula 1, wherein
A denotes a double-bonded group selected from among: 
Xxe2x88x92 denotes an anion with a single negative charge selected from among chloride, bromide and methanesulphonate, preferably bromide;
Rand R2 which may be identical or different denote a group selected from methyl and ethyl, which may optionally be substituted by hydroxy or fluorine, preferably unsubstituted methyl;
R3, R4, R5 and R6, which may be identical or different, denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine or bromine;
R7 denotes hydrogen, methyl, ethyl, methyloxy, ethyloxy, CF3, or fluorine.
Preferred compounds of general formula 1 according to the invention are those wherein
A denotes a double-bonded group selected from among: 
Xxe2x88x92 denotes bromide;
R1 and R2 which may be identical or different denote a group selected from methyl and ethyl, preferably methyl;
R3, R4, R5 and R6, which may be identical or different, denote hydrogen, methyl, methyloxy, chlorine or fluorine;
R7 denotes hydrogen, methyl or fluorine.
Of particular importance according to the invention are compounds of general formula 1, wherein
A denotes a double-bonded group selected from among: 
Xxe2x88x92 denotes bromide;
R1 and R2 which may be identical or different denote methyl or ethyl, preferably methyl;
R3, R4, R5 and R6, which may be identical or different, denote hydrogen or fluorine, preferably hydrogen;
R7 denotes hydrogen, methyl or fluorine, preferably methyl or fluorine, most preferably methyl.
The invention relates to the compounds of formula 1, optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates thereof.
In the compounds of general formula 1 the groups R3, R4, R5 and R6, provided that they do not denote hydrogen, may each be in the ortho, meta or para position relative to the bond to the xe2x80x9cxe2x80x94Cxe2x80x94R7xe2x80x9d group. Provided that none of the groups R3, R4, R5 and R6 denotes hydrogen, R3 and R5 are preferably linked in the para-position and R4 and R6 are preferably linked in the ortho- or meta-position, most preferably in the meta-position. If one of the groups R3 and R4 and one of the groups R5 and R6 denotes hydrogen, the other group in each case is preferably linked in the meta- or para-position, most preferably in the para-position. If none of the groups R3, R4, R5 and R6 denotes hydrogen, according to the invention the compounds of general formula 1 wherein the groups R3, R4, R5 and R6 have the same meaning are particularly preferred.
Of particular importance according to the invention are the compounds of general formula 1 wherein the ester-substituent on the nitrogen-bicyclic group is in the -configuration. These compounds correspond to general formula 1-: 
According to the invention, the following compounds are of particular importance:
tropenol 2,2-diphenylpropionate-methobromide;
scopine 2,2-diphenylpropionate-methobromide;
scopine 2-fluoro-2,2-diphenylacetate-methobromide;
tropenol 2-fluoro-2,2-diphenylacetate-methobromide;
Unless otherwise stated, the alkyl groups are straight-chained or branched alkyl groups having 1 to 4 carbon atoms. The following are mentioned by way of example: methyl, ethyl, propyl or butyl. In some cases the abbreviations Me, Et, Prop or Bu are used to denote the groups methyl, ethyl, propyl or butyl. Unless otherwise stated, the definitions propyl and butyl include all the possible isomeric forms of the groups in question. Thus, for example, propyl includes n-propyl and iso-propyl, butyl includes iso-butyl, sec.butyl and tert.-butyl, etc.
Unless otherwise stated, the alkylene groups are branched and unbranched double-bonded alkyl bridges having 1 to 4 carbon atoms. The following are mentioned by way of example: methylene, ethylene, propylene or butylene.
Unless otherwise stated, the alkylene-halogen groups are branched and unbranched double-bonded alkyl bridges having 1 to 4 carbon atoms which are mono-, di- or trisubstituted, preferably monosubstituted, by a halogen. Accordingly, unless otherwise stated, the alkylene-OH groups are branched and unbranched double-bonded alkyl bridges having 1 to 4 carbon atoms which are mono-, di- or trisubstituted, preferably monosubstituted, by a hydroxy.
Unless otherwise stated, the term alkyloxy groups denotes branched and unbranched alkyl groups having 1 to 4 carbon atoms which are linked via an oxygen atom. Examples of these include: methyloxy, ethyloxy, propyloxy or butyloxy. The abbreviations MeOxe2x80x94, EtOxe2x80x94, PropOxe2x80x94 or BuOxe2x80x94 are used in some cases to denote the groups methyloxy, ethyloxy, propyloxy or butyloxy. Unless otherwise stated, the definitions propyloxy and butyloxy include all possible isomeric forms of the groups in question. Thus, for example, propyloxy includes n-propyloxy and iso-propyloxy, butyloxy includes iso-butyloxy, sec.butyloxy and tert.-butyloxy, etc. In some cases, within the scope of the present invention, the term alkoxy is used instead of the term alkyloxy. Accordingly, the terms methoxy, ethoxy, propoxy or butoxy may also be used to denote the groups methyloxy, ethyloxy, propyloxy or butyloxy
Unless otherwise stated, the term alkylene-alkyloxy groups denotes branched and unbranched double-bonded alkyl bridges having 1 to 4 carbon atoms which are mono-, di- or trisubstituted, preferably monosubstituted, by an alkyloxy group.
Unless otherwise stated, the term xe2x80x94Oxe2x80x94CO-alkyl groups denotes branched and unbranched alkyl groups having 1 to 4 carbon atoms which are linked via an ester group. The alkyl groups are linked directly to the carbonyl carbon of the ester group. The term xe2x80x94Oxe2x80x94CO-alkyl-halogen group should be understood in the same way. The group xe2x80x94Oxe2x80x94COxe2x80x94CF3 denotes trifluoroacetate.
Halogen within the scope of the present invention denotes fluorine, chlorine, bromine or iodine. Unless stated otherwise, fluorine and bromine are the preferred halogens. The group CO denotes a carbonyl group.
The compounds according to the invention may partly be prepared, as illustrated below, analogously to procedures which are already known from the prior art (Diagram 1). The carboxylic acid derivatives of formula 3 are known in the art or may be obtained using methods of synthesis known in the art. If only suitably substituted carboxylic acids are known in the art, the compounds of formula 3 may also be obtained directly from them by acid- or base-catalysed esterification with the corresponding alcohols or by halogenation with the corresponding halogenation reagents. 
Diagram 1
Starting from the compounds of formula 2 the esters of general formula 4 may be obtained by reacting the carboxylic acid derivatives of formula 3, wherein R may denote chlorine or a C1-C4-alkyloxy group, for example. When R denotes C1-C4-alkyloxy this reaction may be carried out, for example, in a sodium melt at elevated temperature, preferably at about 50-150xc2x0 C., most preferably at about 90-100xc2x0 C. at low pressure, preferably below 500 mbar, most preferably below 75 mbar. Alternatively, instead of the derivatives 3 wherein R denotes C1-C4-alkyloxy, the corresponding acid chlorides (R equals Cl) may be used.
The compounds of formula 4 thus obtained may be converted into the target compounds of formula 1 by reacting the compounds R2xe2x80x94X, wherein R2 and X may be as hereinbefore defined. This synthesis step may also be carried out analogously to the examples of synthesis disclosed in WO 92/16528.
Alternatively to the procedure illustrated in Diagram 1 for synthesising the compounds of formula 4, the derivatives 4 in which the nitrogen bicyclic group is a scopine derivative may be obtained by oxidation (epoxidation) of compounds of formula 4 wherein the nitrogen-bicyclic group is a tropenyl group. This may be done as follows, according to the invention.
Compound 4, wherein A denotes xe2x80x94CHxe2x95x90CHxe2x80x94, is suspended in a polar organic solvent, preferably in a solvent selected from among N-methyl-2-pyrrolidone (NMP), dimethylacetamide and dimethylformamide, preferably dimethylformamide, and then heated to a temperature of about 30-90xc2x0 C., preferably 40-70xc2x0 C. Then a suitable oxidising agent is added and the mixture is stirred at constant temperature for 2 to 8 hours, preferably 3 to 6 hours. The preferred oxidising agent is vanadium pentoxide mixed with H2O2, most preferably H2O2-urea complex combined with vanadium pentoxide. The mixture is worked up in the usual way. The products may be purified by crystallisation or chromatography, depending on their crystallisation tendencies.
Alternatively, the compounds of formula 4 wherein R7 denotes halogen may also be obtained by the method shown in Diagram 2. 
Diagram 2
For this, the benzilic acid esters of formula 5 [verb missing (are converted?)], using suitable halogenating reagents, into the compounds 4 wherein R7 denotes halogen. The reaction of halogenation to be carried out according to Diagram 2 is already sufficiently well known in the art.
The benzilic acid esters of formula 5 may be obtained in accordance with or analogously to methods known in the art (see e.g. WO 92/16528).
As shown in Diagram 1, the intermediate products of general formula 4 are of crucial importance. Accordingly, in another aspect, the present invention relates to the intermediates of formula 4: 
wherein
A denotes a double-bonded group selected from among: 
R1 denotes C1-C4-alkyl, which may optionally be substituted by hydroxy or halogen;
R3, R4, R5 and R6, which may be identical or different, denote hydrogen, C1-C4-alkyl, C1-C4-alkyloxy, hydroxy, CF3, CN, NO2 or halogen;
R7 denotes hydrogen, C1-C4-alkyl, C1-C4-alkyloxy, C1-C4-alkylene-halogen, halogen-C1-C4-alkyloxy, C1-C4-alkylene-OH, CF3, xe2x80x94C1-C4-alkylene-C1C4-alkyloxy, xe2x80x94Oxe2x80x94COC1-C4-alkyl, xe2x80x94Oxe2x80x94COC1-C4-alkyl-halogen, xe2x80x94Oxe2x80x94COCF3 or halogen, while 
if A denotes
R1 denotes methyl and
R3, R4, R5 and R6 denote hydrogen,
R7 cannot be n-propyl.
Preferred are compounds of general formula 4, wherein
A denotes a double-bonded group selected from among: 
R1 denotes a group selected from among methyl, ethyl, n-propyl and iso-propyl, which may optionally be substituted by hydroxy or fluorine, preferably unsubstituted methyl;
R3, R4, R5 and R6, which may be identical or different, denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CN, CF3 or NO2;
R7 denotes hydrogen, methyl, ethyl, methyloxy, ethyloxy, xe2x80x94CH2xe2x80x94F, xe2x80x94CH2xe2x80x94CH2xe2x80x94F, xe2x80x94Oxe2x80x94CH2xe2x80x94F, xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94F, xe2x80x94CH2xe2x80x94OH, xe2x80x94CH2xe2x80x94CH2xe2x80x94OH, CF3, xe2x80x94CH2xe2x80x94OMe, xe2x80x94CH2xe2x80x94CH2xe2x80x94OMe, xe2x80x94CH2xe2x80x94OEt, xe2x80x94CH2xe2x80x94CH2xe2x80x94OEt, xe2x80x94Oxe2x80x94COMe, xe2x80x94Oxe2x80x94COEt, xe2x80x94Oxe2x80x94COCF3, xe2x80x94Oxe2x80x94COCF3, fluorine, chlorine or bromine.
Particularly preferred are compounds of general formula 4, wherein
A denotes a double-bonded group selected from among: 
R1 denotes a group selected from methyl and ethyl, which may optionally be substituted by hydroxy or fluorine, preferably unsubstituted methyl;
R3, R4, R5 and R6, which may be identical or different, denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine or bromine;
R7 denotes hydrogen, methyl, ethyl, methyloxy, ethyloxy, CF3, or fluorine.
Preferred compounds of general formula 4 according to the invention are those wherein
A denotes a double-bonded group selected from among: 
R1 denotes a group selected from methyl and ethyl, preferably methyl;
R3, R4, R5 and R6, which may be identical or different, denote hydrogen, methyl, methyloxy, chlorine or fluorine;
R7 denotes hydrogen, methyl or fluorine.
Of particular importance according to the invention are compounds of general formula 4 wherein
A denotes a double-bonded group selected from among: 
R1 denotes methyl or ethyl, preferably methyl;
R3, R4, R5 and R6, which may be identical or different, denote hydrogen or fluorine, preferably hydrogen;
R7 denotes hydrogen, methyl or fluorine, preferably methyl or fluorine, most preferably methyl.
As in the compounds of general formula 1, in the intermediates of formula 4, the groups R3, R4, R5 and R6, provided that they do not denote hydrogen, may each be in the ortho, meta or para position relative to the bond to the xe2x80x9cxe2x80x94Cxe2x80x94R7xe2x80x9d group. Provided that none of the groups R3, R4, R5 and R6 denotes hydrogen, R3 and R5 are preferably linked in the para-position and R4 and R6 are preferably linked in the ortho- or meta-position, most preferably in the meta-position. If one of the groups R3 and R4 and one of the groups R5 and R6 denotes hydrogen, the other group in each case is preferably linked in the meta- or para-position, most preferably in the para-position. If none of the groups R3, R4, R5 and R6 denotes hydrogen, according to the invention the intermediates of general formula 1 wherein the groups R3, R4, R5 and R6 have the same meaning are particularly preferred.
The examples of synthesis described hereinafter serve to illustrate the present invention still further. However, they are intended only as examples of procedures as an illustration of the invention without restricting the invention to the subject-matter described by way of example.